Amino acids such as L-glutamic acid and L-aspartic acid are known to be central nervous system neurotransmitters. It is said that extracellular accumulation of these excitatory amino acids and their continuous of excessive stimulation of the nerves lead to Huntington chorea, Parkinson disease, epilepsy, Alzheimer disease, senile dementia or neurodegeneration or deficiency in mental and motor functions observed after the condition of cerebral ischemia, oxygen deficiency or hypoglycemia.
It has come to be considered that a regulator of the abnormal activity of an excitatory amino acid is useful for the therapeutic treatment of neurodegeneration or psychic diseases.
Excitatory amino acids exhibit their action through glutamate receptors which are specific receptors existing at postsynapse or presynapse. At present, such receptors can be classified into three groups based on electrophysiological and neurochemical studies.
1) NMDA (N-methyl-D-aspartate) receptor PA1 2) non-NMDA receptor PA1 3) metabotropic glutamate receptor PA1 X: a nitrogen atom or a group represented by the formula CH, PA1 R: an imidazolyl group or a di-lower alkylamino group, PA1 R.sup.1 : (1) a halogen atom, a nitro group, a cyano group, a carboxyl group, an amino group, a mono- or di-lower alkylamino group, a lower alkanoyl group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group or a carbamoyl group, PA1 R.sup.2 : a hydroxyl group, a lower alkoxyl group, an amino group or a mono- or di-lower alkylamino group, PA1 A: a lower alkylene group which may be substituted or a group represented by the formula --O--B--, and PA1 B: a lower alkylene group, PA1 (1) a halogen atom, a nitro group, a cyano group, a mono- or di-lower alkylamino group, a lower alkylsulfinyl group, a lower alkylsulfonyl group or a carbamoyl group, PA1 (2) a lower alkyl or lower alkoxyl group which may be substituted by a carboxyl group or an aryl group, and PA1 (3) a phenyloxy group which may be substituted by a lower alkoxycarbonyl group. PA1 Y.sup.1 : a halogen atom other than a fluorine atom PA1 R.sup.1 ': a hydrogen atom and a group represented by the above R.sup.1, PA1 R.sup.3 : a lower alkyl group, PA1 Z.sup.1, Z.sup.2 : a hydrogen atom and a group represented the formula R.sup.3 COCO--, with the proviso that both of Z.sup.1 and Z.sup.2 are not hydrogen atoms at the same time.
a) AMPA [2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid] receptor PA2 b) kainate receptor PA2 (2) a lower alkyl group or lower alkoxyl group which may be substituted by a halogen atom(s), a carboxyl group(s) or an aryl group(s), PA2 (3) a phenyloxy group which may be substituted by a lower alkoxycarbonyl group or a carboxyl group,
The compound according to the present invention has glutamate receptor antagonizing action and inhibitory action against kainic acid neurotoxicity and is useful as an anti-ischemia or as an psychotropic.
L-glutamic acid or L-aspartic acid activates the above-described glutamate receptors and transmits excitation. When an excess amount of NMDA, AMPA or kainic acid is caused to act on the neuron, neuronal death occurs. It is reported that 2-amino-5-phosphonovalerianic acid or 2-amino-7-phosphonoheptanic acid which is a selective antagonist against the NMDA receptor is effective for experimental animal models suffering from neuropathy, epilepsy or cerebral ischemia (J. Pharmacology and Experimental Therapeutics, 250, 100 (1989); J. Pharmacology and Experimental Therapeutics, 240, 737 (1987); or Science, 226, 850 (1984)).
It is reported that NMDA receptor functions are allosterically regulated by a glycine receptor (Eur. J. Pharmacol., 126, 303 (1986)), while it is reported that HA-966 which is an antagonist against the glycine receptor is effective in experimental animal models suffering from cerebral ischemia (Annual meeting of Society for Neuroscience, 1989).
It is also reported that NBQX (6-nitro-7-sulfamoylbenzo[f]quinoxaline) which is a selective antagonist against the AMPA receptor is also effective in experimental animal models suffering from cerebral ischemia (Science, 247, 571 (1990)).
On the other hand, it has been shown that all the non-NMDA receptors subjected to cloning have affinity with kainic acid and it is suggested that among these receptors, a receptor having low affinity with kainic acid (the AMPA/kainate receptor) has a relation with neuronal death at the time of ischemia such as cerebral infarction (P. C. May and P. M. Robison, J. Neurochem., 60, 1171-1174 (1933)). This AMPA/kainate receptor has high affinity with AMPA but the binding sites of AMPA and kainic acid are not known. It is however reported that AMPA and kainic acid exhibit different electrophysiologic responses against the AMPA/kainate receptor. It is reported that in a neuronal toxicity test using a neuronal culture system, kainic acid itself causes marked neuronal cell death, while the action of AMPA alone is weak (P. C. May and P. M. Robison, J. Neurochem., 60, 1171-1174 (1993)). Accordingly, there is a possibility that neuronal death caused by excessive excitation by glutamic acid at the time of ischemia is intensely suppressed by a compound having inhibitory action against kainic acid toxicity in the neuronal culture system.
There are several reports on diketoquinoxaline derivatives having an NMDA-glycine receptor antagonizing action and/or AMPA receptor antagonizing action (an unexamined published Japanese patent application (kokai) No. 63-83074, an unexamined published Japanese patent application (kokai) No. 63-258466, an unexamined published Japanese patent application (kokai) No. 1-153680, an unexamined published Japanese patent application (kokai) No. 2-48578, an unexamined published Japanese patent application (kokai) No. 2-221263, an unexamined published Japanese patent application (kokai) No. 2-221264, an international patent publication WO92/07847 and an international patent publication WO93/08173).